Melphalan and chlorambucil are two structurally related anticancer drugs that are used to treat a wide variety of malignancies. Melphalan is effective in the treatment of multiple myeloma, ovarian carcinoma, as adjuvant chemotherapy of stage II breast carcinoma, and in the regional perfusion of nonresectable melanoma. Chlorambucil is used in the treatment of chronic lymphocytic leukemia, carcinoma of the breast and ovary, and Hodgkin's and non-Hodgkin's lymphomas. Both drugs are classical bifunctional alkylating agents. Melphalan is a nitrogen mustard derivative of the large neutral amino acid L-phenylalanine, and chlorambucil is structurally similar to melphalan but lacks an amine moiety.
Unfortunately, both chlorambucil and melphalan only minimally enter the brain, which is a major site in the development of metastases, causing death. The blood-brain barrier is a significant barrier to the entry of water-soluble or ionized compounds from the bloodstream into the brain. Many pharmaceutically active compounds, do not reach the brain, where they may be most effective.
The brain is a major site in the metastatic cascade process. The incidence of metastases to the brain from the ovary, breast, and melanoma, for which melphalan and chlorambucil are administered, are approximately 5%, 10%, and 40%, respectively.
Although chlorambucil and melphalan have been used extensively in the clinic for over 20 years, it has been found that melphalan becomes hydrolyzed after administration to humans or rats to its monohydroxy and dihydroxy products, the latter having no cancer activity. Chlorambucil undergoes beta-oxidation in vivo, to yield the active metabolite phenylacetic mustard via the active intermediate 3,4-dehydro chlorambucil. However, neither of these compounds passes the blood-brain barrier. Hence, they are not useful in the treatment of brain tumors.
Speeter et al., in U.S. Pat. No. 2,821,540, disclose a method of preparing esters of 4-aminobenzoic acid which are not easily hydrolyzed in vivo. The carboxylate group of these esters is hindered by adding to at least one of the carbon atoms ortho to the carboxylate group in the 1-position of a substituent selected from the group consisting of alkyl, cycloalkyl, aralkyl, aryl, and heterocyclic radicals.
Because chlorambucil and melphalan are effective drugs for the treatment of a variety of cancers, attempts have been made to direct the drugs directly to the affected site.
Yoshida et al., in U.S. Pat. No. 4,584,136, disclose Estracyt compounds having carcinostatic agents such as chlorambucil bound thereto for transporting the active agent directly to the tumor site.
Asano et al, in U.S. Pat. No. 4,332,797, disclose chlorambucil derivatives which are obtained by chemically binding chlorambucil to an estradiol or derivative to direct the drug more specifically to cancer cells in the body.